This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 1/10/2008 Hypothesis: In patients with sporadic ALS, pyrimethamine will reduce SOD1 levels in lymphocytes and cerebrospinal fluid at doses of 100 mg of less. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing relentlessly progressive weakness of the arms, legs and respiratory muscles that is uniformly fatal. There are approximately 30,000 patients living with ALS. There is no treatment. The cause is uncertain in most patients. Three percent of patients have a familial form of ALS (FALS) that is caused by a mutation in the gene coding for the free radical scavenging enzyme copper/zinc superoxide dismutase (SOD1). The exact mechanism of how the mutant SOD1 causes the disease is uncertain. However, the SOD1 is definitely integral in the pathogenesis of FALS because inserting the SOD1 mutant gene into mice causes a disease closely resembling ALS;inhibiting expression of the SOD1 gene prevents animals from developing the disease;and increasing or decreasing the number of mutated genes proportionately speeds or slows the progression of the disease. Reducing SOD1 in the mouse model of FALS attenuates the disease proportionate to the degree of SOD1 reduction. The role that SOD1 plays in sporadic ALS (SALS) is uncertain. However, it is possible that either through mutation, oxidative stress, or some other factor, SOD1 may sustain molecular damage which confers an enhanced propensity to cause oxidative damage, impair processing of the protein through the proteasome and lysosomal system, and alter cellular metabolism eventually causing cell death. Accordingly, lowering of SOD1 levels in sporadic ALS may result in slowing of the disease process. Through an extensive in vitro screening program for medications having the ability to reduce SOD1 levels, several molecules that reduce SOD1 protein levels are now known. One of the most potent molecules is pyrimethamine, an FDA approved medication used for the treatment of malaria and toxoplasmosis. Pyrimethamine dramatically reduces SOD1 levels in mice and our preliminary studies show similar findings in humans. This study's primary objective is to evaluate the safety and tolerability of pyrimethamine in patients with sporadic ALS. Secondary objectives will be to determine dose optimization for maximal SOD1 level reduction. Ten (10) patients with mild to moderate sporadic ALS will receive up to 100mg of pyrimethamine for 44 weeks. Change in Appel ALS score, ALS-FRSr, quality of life and motor unit estimates (MUNE) will also be measured.